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Year : 2022  |  Volume : 65  |  Issue : 4  |  Page : 832-838
Molecular stratification of high-grade urothelial carcinoma by immunohistochemistry with its histomorphological and clinical correlation

1 Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
2 Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India

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Date of Submission27-Jan-2021
Date of Decision24-May-2021
Date of Acceptance24-May-2021
Date of Web Publication06-Jun-2022


Introduction: Urothelial carcinoma poses a significant cause of morbidity and mortality. The recent classification of Tumors of Urinary System by World Health Organization fourth edition) has elucidated its molecular subtypes and its associated prognostic significance. Methods: We used immunohistochemistry marker expression (CK5/6, CK20, CD44, EGFR) as a surrogate marker, to stratify 150 cases of high-grade urothelial carcinoma into the intrinsic molecular subtypes. A correlation was also done with immunohistochemical markers p53, p21, E-cadherin and Ki-67. Results: On subtyping, 47.3% cases were basal, 42.7% luminal and 10% remained unclassified. We did not find GATA3 useful for molecular stratification in our study. Muscle invasion was seen in 59% of basal and 31% of luminal subtype (P = 0.016). Squamous differentiation was most commonly associated with basal subtype (P < 0.001). EGFR expression was seen in 62% of basal and 38% of luminal subtype (P = 0.014), and thus can be used as an additional marker for molecular stratification. Overexpression of p53 was seen in 64% cases of muscle invasive and 36% of non-muscle invasive high-grade carcinomas (P < 0.0001). An inverse relationship was observed between p53 and p21 immunoexpression (r = –0.494) (P < .0001). The overall survival at 1- and 2-year interval was more in the luminal subtype, suggesting an early mortality in basal group, (P = 0.827), and at 6 years both the groups had almost similar results. Conclusion: High-grade urothelial carcinoma is challenging in terms of therapeutic strategy. Increased understanding of underlying molecular basis helps identifying targetable treatment options, and newer biomarkers will enhance predictive and prognostic stratification.

Keywords: High-grade, immunohistochemistry, molecular stratification, urothelial carcinoma

How to cite this article:
Gupta G, Gupta R, Pasricha S, Sharma A, Durga G, Kamboj M, Tripathi R, Mehta A. Molecular stratification of high-grade urothelial carcinoma by immunohistochemistry with its histomorphological and clinical correlation. Indian J Pathol Microbiol 2022;65:832-8

How to cite this URL:
Gupta G, Gupta R, Pasricha S, Sharma A, Durga G, Kamboj M, Tripathi R, Mehta A. Molecular stratification of high-grade urothelial carcinoma by immunohistochemistry with its histomorphological and clinical correlation. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Nov 30];65:832-8. Available from:

   Introduction Top

Urothelial carcinoma (UC) is the most common histological type of bladder cancer, which accounts for about 90% and 80% of bladder cancers in industrialized countries and other parts of the world, respectively.[1] UC is the tenth most common cancer worldwide and the sixth most common among males, being four times more prevalent in males.[2]

Low-grade and noninvasive UC usually present with a low stage with favorable outcome, whereas high-grade UC (HGUC), especially muscle-invasive bladder cancer (MIBC), is a significant cause of morbidity and mortality. Nonmuscle invasive bladder cancers (NMIBC) comprise 70%–80% of bladder cancers at the time of diagnosis and are not life threatening. They are treated by transurethral resection followed by intravesical BCG or mitomycin, but have a tendency to recur. In contrast, high-grade MIBC, comprising 30% of UC, is an aggressive entity, with poor disease-free survival and overall survival, accounting for significant morbidity and mortality.[3],[4],[5]

Radical cystectomy with perioperative cisplatin-based combination chemotherapy is the current standard of care for high-risk MIBC, which is only effective in 30%–40% of cases, and it is not yet possible to identify the patients who are more likely to obtain benefit.[4] No effective alternative to chemotherapy-resistant tumors has been identified.[5]

Rapidly evolving genomic paradigm is a new approach to prognosis which aims to identify the carcinomas with more aggressive biology, which do not respond to the conventional treatment. Recently, the World Health Organization (WHO) classification of Tumors of Urinary System (fourth edition, 2016) has incorporated molecular taxonomy of bladder cancer, elaborating the molecular subtypes of UC into basal, luminal and p53 like subtype.[6] On the basis of immunohistochemical expression, we have stratified 150 cases of high-grade urothelial carcinoma (HGUC) into basal and luminal subtypes by using IHC makers for CK5/6, CD44, CK20, and EGFR. These findings were correlated with clinico-pathological profiles, and we also evaluated the prognosis of these subtypes along with other prognostic IHC biomarkers (Ki-67, p53, E-cadherin and p21).

This is the first study from an Indian oncology center to stratify HGUC into molecular subtypes using IHC stains.

   Methods Top

This retrospective, observational study was performed at a tertiary cancer care center in 150 consecutively diagnosed HGUC cases within a duration of 2 years (January 2014 to December 2015), and with a median follow-up of 6 years. The formalin-fixed paraffin-embedded (FFPE) blocks were retrieved from the archives, and histomorphological features were assessed to reaffirm the diagnosis, grading and staging of HGUC. Further, they were subjected to eight IHC markers (CK5/6, CK20, CD44, p53, p21, EGFR, E-cadherin, and Ki-67). The details of various primary antibodies used, with manufacturer, clones, dilution, staining pattern, and reporting positive cut-off threshold of immune-expression used have been tabulated in [Table 1]. The threshold cut-off used for Ki67 was 20%, as mentioned by Thakur et al.[7] For p21 the threshold of 50% is defined as high expression by Stein et al.[8] For P53 the complete loss of expression or 50% expression is defined as strong homogeneous staining by Esrig et al.[9] For CK5/6, CK20, CD44, and E- Cadherin, a threshold of 20% was taken, as it helps in stratification of UC, as shown by study of Dhadhania et al.[10] In their study, the tumors were grouped into two distinct groups in accordance with different cut-off quantitative immune-expression (10%, 20%, 30%, and 40%), with best results at 20% cut-off. Threshold taken for EGFR was >10%, as defined for oral carcinoma by Bernardes et al.[11]
Table 1: Specification of primary monoclonal antibodies uses for immunohistochemistry

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All IHC tests were performed on Ventana Benchmark XT (ROCHE), using heat-induced antigen epitope retrieval technique and ultraview labelling system, and were evaluated with appropriate internal positive and negative batch controls. The percentage of positive cells and their intensity of staining were recorded for every case. Membranous staining scoring was applied for EGFR, as is used in evaluation of head and neck squamous cell carcinoma.[12] Immunoscoring and results were recorded by 3 histopathologists (GG, RG, and SP) and in case of any discrepant opinion a consensus result was obtained. The cases were classified as basal subtype (positive for CK5/6, CD44, and EGFR, negative for CK20), and luminal subtype (positive for CK20, negative for CK5/6, and CD44), as shown in the algorithm [Figure 1]a. Those with dual negativity or positivity were labelled as unclassified. The clinico-pathological profile of patients was recorded and correlated with these subtypes.
Figure 1: (a) Algorithm used for subtyping cases of high-grade urothelial carcinoma into intrinsic molecular subtypes using Immunohistochemistry. (b) Graph depicting the expression of immunohistochemical markers in the basal and luminal subtypes of high-grade urothelial carcinoma (n = 135)

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Besides the descriptive statistics to be presented as summary, quantitative variables were compared using unpaired t-test/Mann–Whitney Test (according to the distribution of data) between the two groups. Qualitative variables were correlated using Chi-Square test/Fisher's exact test. Kaplan–Meier survival analysis was used to find overall survival (OS). Log-rank test was used to compare the survival distributions of two samples. A P value of < 0.05 was considered statistically significant. The Statistical Package for the Social Sciences (SPSS) software program, version 23.0 was used for all statistical analysis.

All procedures performed in the current study were approved by Institutional Review board (IRB) (reference number RGCIRC/IRB/67/2016, May 17, 2016) in accordance with the 1964 Helsinki declaration and its later amendments.

Formal written informed consent was not required with a waiver by the appropriate IRB, as study required only FFPE tissue specimen which can be used for research purpose, consent being taken from every patient at the time of hospital admission as an institutional policy.

   Results Top

In the present study of 150 cases, the mean age of patients was 65.3 years (age range of 36 to 90 years), constituting a majority of male patients (125 cases, 83%).

On light microscopic examination, 134 cases (89%) were invasive, and 16 (11%) were noninvasive papillary UC. Among these 47.3% (71 cases) were MIBC, whereas 52.7% (79 cases) were NMIBC. Out of 134 invasive cases, 71 cases (53%) were MIBC (stage T2 to T4), and 63 cases (47%) were stage T1 lesion, limited to subepithelial connective tissue (NMIBC). Expression of all applied IHC markers was observed [Table 2].
Table 2: Immunohistochemical profile of high-grade urothelial carcinoma cases (n=150)

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The cases were stratified using IHC as a surrogate marker for intrinsic molecular subtyping of UC, as per the mentioned algorithm [Figure 1]a. Of the total 150 cases, 71 cases (47.3%) were positive for CK5/6, CD44, and EGFR, and were classified as basal subtype [Figure 2]; and 64 cases (42.7%) were positive for CK20 whereas negative for basal markers, and were classified as luminal subtype [Figure 3]. The remaining 15 cases (10%) that were negative for both CK20 and CK5/6 were labelled as unclassified.
Figure 2: (a) Microphotograph of basal subtype Urothelial Carcinoma (H andE; 200×). Immunohistochemical stains show strong cytoplasmic CK5/6 expression (b), CD44 membranous positivity (c), and EGFR membranous expression (d)

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Figure 3: (a) Microphotograph of luminal subtype Urothelial Carcinoma (H and E; 100×). Immunohistochemical stains show strong cytoplasmic CK20 expression (b), and negative CK5/6 in tumor cells (c)

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Of all the MIBC (n = 71) cases, 59%, 31%, and 10% were in the basal, luminal and unclassified category, showing a statistically significant preponderance in basal subtype (P = 0.016).

Among the p53 positive (overexpression/null expression; n = 74) category, majority of the cases (64%) were MIBC (P < .0001). On contrary in p21 immunopositive category (n = 59), the majority (73%) of cases were NMIBC (73%) as compared to MIBC (27%), which was statistically significant, (P < 0.0001). An inverse relationship was observed between p53 and p21 immunoexpression (r = –0.494).

The expression of EGFR, E-cadherin and p53 was correlated in basal and luminal subtypes (n = 135). The expression of EGFR expression was significant in the basal subtype (62%, 49 cases) as compared to luminal subtype (38%, 30 cases), (P = 0.014). E-cadherin expression in the basal category (52%, 64 cases) was almost similar to that in luminal subtype (48%, 59 cases); (P = 0.768). Similarly, p53 positive cases in the basal category (56%, 38 cases) were marginally more than in luminal subtype (44%, 30 cases); (P = 0.492). High Ki-67 expression (>20%) was also similar in basal (30.4%, 41 cases) and luminal (29.6%, 40 cases), (P = 0.350), and almost same number in MIBC and NMIBC cases (P = 0.403); [Figure 1]b.

Squamous differentiation was seen in 20/150 cases, and 80% of these (16 cases) were of basal subtype (P < 0.001).

Metastatic lymph node involvement was seen in 6% (4/71) cases of basal subtype, and 12.5% (8/64) cases of luminal subtype, the association was not statistically significant (P = 0.227). Systemic metastasis was seen 5.6% and 6% of basal and luminal subtypes, respectively, without any statistical significance.

Out of 150 cases of HGUC, 50 cases received BCG therapy or mitomycin therapy, 57 received surgical therapy, 8 received chemotherapy alone, 23 were not given any therapy, and 12 received dual treatment modalities.

As depicted in Kaplan–Meier survival analysis [Figure 4]a, the overall survival (OS) of patients in our study after a median follow-up of 6 years was 52%. Among the intrinsic subtypes, the OS at the end of 1 year and 2 years was 66% and 59%, respectively, in the basal group, whereas it was 83% and 72%, respectively, in the luminal group. This suggested an early mortality in basal group; however, was not statistically significant (P = 0.827). The OS at 6 years was 53% and 48% in the basal and luminal groups, respectively.
Figure 4: (a) Kaplan-Meier survival analysis graph for overall survival (OS) in patients with the intrinsic basal and luminal subtypes of urothelial carcinoma (n=135). {Abberviation: OS- overall survival} (b) Kaplan-Meier survival analysis graph analysing overall survival (OS) with tumor stage, nodal stage, carcinoma-in-situ (CIS), variant histology and type of surgery

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The Kaplan–Meier survival analysis was done for tumor stage (Ta, T1, and T2-4), the OS was statistically significant (P = 0.015) for the T-stage, with worse OS of 38% at 5 years in muscle-invasive (T2-T4) and 88% for Ta stage. Similarly, for nodal staging (N0 and N1-2), the OS was statistically significant (P = 0.033), with worse OS of 30% at 5 years in N1-2 cases and 56% in N0 cases. The presence of CIS, variant histology, and type of sample did not yield any difference in OS (P values 0.699, 0.994, and 0.798, respectively) [Figure 4]b.

The recurrence/progression between various groups could not be evaluated because of numerically small number of such events in cases where follow-up was available; hence a meaningful statistical analysis was not possible. Most of patients who were lost to follow-up were contacted telephonically for update on their survival status, and many relatives preferred not to discuss their disease status any further. Hence, only their OS status could be updated.

   Discussion Top

The bladder cancer reveals complex genomic alterations with heavy mutational load, and distinct genomic signatures associated with cancer progression, metastasis, and poor response to therapy.[13],[14] UC show heterogenous clinical behavior owing to their distinct molecular pathogenesis in invasive and noninvasive UC.[14]

Many studies have evaluated the molecular underpinnings, role of oncogenes, tumor suppressor genes, and chromosomal alterations to identify the novel genetic events in UC, especially high-grade MIBC.[4],[10],[14]

Low-grade papillary tumors and NMIBC usually have activating mutations in HRAS, fibroblast growth factor receptor 3 (FGFR3) genes, and CDKNA1 (p21), and are genomically stable.[13],[15],[16] NMIBC also show loss of heterozygosity (LOH) of chromosome 9q.[14]

In contrast, HGUC and MIBC are genomically unstable, and arise from high-grade dysplasia/carcinoma-in-situ (CIS).[13],[15],[16] Both, CIS and invasive tumors, are characterized by homozygous deletion of p16INK4a, and frequent alterations in the TP53 and retinoblastoma (RB) gene pathways.[14] Occasional transformation of a noninvasive papillary tumor to an invasive phenotype, seen in almost 15-20% cases in some studies, occurs with accumulation of additional alterations in the p53 pathway.[5],[10],[14] MIBC also show alterations in cadherins, matrix metalloproteinases (MMPs), vascular endothelial growth factors (VEGFs), and thrombospondin-1 (TSP-1), which contribute to nodal metastasis.[14]

Subtyping patients based on the molecular alterations in their primary tumors permits risk stratification and administration of more personalized therapies.[14] Whole-genome expression profiling has helped to classify bladder cancer into two distinct intrinsic molecular subtypes- basal and luminal, with distinct clinical behavior and prognosis. The MIBC with basal subtype is more aggressive with shorter survival when compared to luminal cancers, and are more sensitive to cisplatin, with better benefits from frontline chemotherapy as compared to luminal subtypes.[10],[13]

However, these complex classifications offered by expression profiling, proteomics, exome sequencing and mutational studies on whole genome are still in realm of large research laboratories. Few studies have done molecular stratification of UC using IHC markers into these two major subtypes, basal and luminal. As per the prevailing literature in NMIBC, there is preponderance of luminal type, whereas in MIBC both basal and luminal types are seen.[5],[10] Expression of high molecular keratins (KRT14, KRT5, KRT6A), and CD44 with basal phenotype (stem cell) and low molecular weight cytokeratin (KRT20 upregulation, GATA3, FOXA1, XBP1, and CD24) with mature (differentiated) luminal type is shown in TGCA and MD Anderson cohorts by expression profiling.[10],[13],[14] The use of IHC to detect qualitatively these proteins expression in the subtypes, as concluded by transcriptomics (expression profiling) correlates with expression of CK5/6, CD44, EGFR, and CK20 on immunohistochemistry.[6] In our study, we used these IHC markers to classify the HGUC into intrinsic subtypes.

In our study population of HGUC (n = 150), mean age was 65.3 years with predominance of males (83%), which was comparable to other studies.[5],[16],[17] On histopathology, 47.3% of the cases were MIBC and 52.7% were NMIBC, with similar findings observed in prior studies.[7],[18]

On molecular subtyping using IHC as a surrogate marker, with a panel of 4 IHC markers (CK5/6, CK20, CD44, and EGFR), our study had a slightly higher number of basal subtype (47.3%), followed by luminal subtype (42.7%) and unclassified (10%). The MD Anderson cancer center (MDACC) discovery cohort (n = 73) of Choi et al.,[5] using both whole-genome mRNA expression profiling and IHC, had 32% basal, 33% luminal and 36% p53-like subtypes.

Dadhania et al.[10] conducted a meta-analysis to identify immunohistochemical signature of the luminal and basal subtypes of bladder cancer, using four cohorts of tumor samples. The three cohorts with fresh frozen tissue included MD Anderson cohort (n = 132), Lund cohort (n = 308), and the Cancer Genome Atlas cohort (TCGA) (n = 408), and one MD Anderson cohort of FFPE tumor tissue (MIBC; n = 89).

On comparison, our findings were at variance with the MD Anderson cohort group, which had predominance of luminal subtype (70% cases) and the basal group comprised 26% of cases. A small fraction of group (4% cases) did not express either luminal or basal markers and were referred to as “double-negative”,[10] which we labeled as “unclassified” in our study.

The Lund cohort study also revealed predominance of luminal subtype (81% cases), whereas only 13% (41 cases) were basal subtype; with findings similar to that of MD Anderson cohort study. With similar classification algorithm, the TCGA cohort group consisted of more of luminal (52%) than basal (44%) subtype.[10]

The MD Anderson cohort study used CK20 and GATA-3 expression for identification of luminal subtype. However, we found expression of GATA-3 in nearly all MIBC cases in both categories with variable staining intensity. Similar findings have been observed by others.[19],[20] Hence, GATA3 was not included as a stratification marker in our algorithm. Moreover, the GATA3 expression may be lost in divergent differentiation and poorly differentiated carcinomas, and the respective clone of GATA3 used may have different sensitivity. The GATA3 clone (L 50-823) used in the present study performed best in NordiQC EQAS program.[21] Thus, the GATA3 clone performance and calibration should be considered before using it for subtyping and for comparison. In our experience, GATA3 is a sensitive marker for suspected metastatic UC. GATA-3 expression is shown to be present in all MIBC basal type carcinoma (C5/6 positive). To prove our point we tested 20 cases of MIBC basal type from our study and noted that 100% tumors expressed GATA-3 diffusely with variable intensity, and hence we excluded GATA-3 from the stratification. The study by Hedegaard et al.[19] and Pena et al.[20] showed expression of GATA-3 in all categories of urothelial tumor classes including basal type.

Choi et al.[5],[13] has mentioned a p53-like subtype, which is determined on gene expression profiling with an active tumor suppressor p53-like gene expression signature, low Myc pathway activation, and low levels of cell cycle and proliferation markers. Dadhania et al.[10] also showed a “p-53 like” signature in a subset of both luminal and basal tumors, and a “claudin-low” subtype with absence of either luminal or basal markers (“double negative”).

The basal subtype is known to show features of squamous differentiation frequently along with up-regulation of markers characteristic of epithelial-to-mesenchymal transition (EMT).[5],[13],[22] Choi et al.[5] reported squamous differentiation in 57% of basal, and 4% of luminal subtypes. In the present study, 22.5% of basal subtype showed squamous differentiation.

Our study showed a strong association of p53 positivity with MIBC (P < .0001), and a similar finding was described by Senol et al.[18] with 64.7% of p53 positive category having MIBC (P = 0.002). Esrig et al.[9] also stated that presence of nuclear p53 overexpression was associated with greater depth of invasion (higher pathological stage). These findings suggest that p53 as an independent and reliable prognostic marker for MIBC.

An inverse relationship is seen between p53 and p21 expression in MIBC, as highlighted by Stein et al.[8] Similar result was seen in our study, with majority of NMIBC (73%) showing p21 positivity (P < 0.0001), with an inverse correlation between over expression of p53 and p21 (r = –0.494).

Lerner et al.[23] and Choi et al.[5] have shown that basal tumors express significant higher levels of EGFR expression. We too observed higher expression of EGFR in basal subtype (62%) as compared to luminal subtype (38%) (P = 0.014).

We could not establish any staging or prognostic stratification with regard to Ki-67 immuno-expression index. The high Ki-67 index (>20%), was seen almost in equal number of cases in both MIBC and NMIBC (P = .403), similar results have been seen in other studies.[7],[24]

Choi et al.[5],[13] study cited association of basal MIBC with metastatic disease at presentation as compared to luminal subtype. We found no such association of basal and luminal subtypes with metastatic nodal involvement and systemic metastasis (P = 0.227). However, as the number of cases with nodal and systemic metastasis were very less, it did not help to establish any association with molecular subtypes.

Patients with basal subtype tend to have more invasive and metastatic disease at presentation. Choi et al.[5] study with MDACC discovery cohort, also showed shorter overall survival of 14.9 months in basal MIBC versus 65.6 months in luminal subtype (P = .098), as well as shorter disease-specific survival of 14.9 months in basal versus 65.6 months in luminal subtype (P = 0.028).

Dadhania et al.,[10] in all four cohorts, reported more aggressive invasive basal tumors as compared to invasive luminal tumors, with significantly shorter survival. We observed better OS in the luminal group at the end of 1 and 2 years, highlighting comparatively aggressive behavior of basal subtype. However, the long-term OS rate at the end of 6 years was similar in the two groups. This is probably due to the fact that the number of events (deaths) and total number of patients in the basal (19/41) and luminal (17/36) groups were almost similar.

Rebola et al.[25] studied 147 T1/Ta bladder carcinoma cases and divided tumors in to four subgroups based on presence of CK5/6 and CK20, namely basal (CK5/6+, CK20-), luminal (CK5/6-, CK20+), null (CK5/6-, CK20-), and mixed (CK5/6+, CK20+). They compared the subgroups for recurrence-free, progression-free and cancer-specific survival. By multivariate analysis, they showed luminal type to be more aggressive phenotype.

With limited resources, IHC for CK5/6 and CK20 would help subtype UCs into basal and luminal type, respectively. As reported by most of studies mentioned in the discussion, CK5/6 expression as a surrogate for basal subtype would indicate an aggressive nature of tumor. Our study had the limitation of unavailability of molecular testing, due to which we were not able to classify cases with “p53-like” subtype. The follow-up data on recurrence/relapse is also incomplete, and thus the same could not be used for identification of more aggressive disease.

   Conclusion Top

Classification of bladder cancer into intrinsic molecular subtypes provides prognostic information. This is the first study from India where we stratified the molecular subtypes of HGUC of the urinary bladder into clinically relevant intrinsic groups of basal and luminal subtypes by using four IHC markers. The basal subtype shows more aggressive behavior, with a strong association with muscle invasion, squamous differentiation, EGFR predominance, p53 positivity, and early mortality.

The identification of these intrinsic subtypes, reminiscent of breast carcinoma, has ignited further interest in classifying the UC into subtypes, for prognostication and to predict treatment response. Hence, further larger studies and cohorts are required to formulate the usage of IHC panels for molecular subtyping of bladder cancer with distinct prognostic and therapeutic implications.


We would like to thank Ms Sangeeta Arora and Mr Arvind Bhunker for performing the IHC stains, Mr Ajay for block retrieval and archival, and Mr Tulsi Ram for microtomy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Meenakshi Kamboj
Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi – 110 085
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_95_21

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